A Phase I Biodistribution and Pharmacokinetic Trial of Humanized Monoclonal Antibody Hu3s193 in Patients with Advanced Epithelial Cancers that Express the Lewis-Y Antigen

Abstract

). The first infusion of hu3S193 was trace labeled with Indium-111, and biodistribution, pharmacokinetics, tumor uptake, and immune response were evaluated in all patients. Results: A total of 15 patients (7 male/8 female; age range, 42-76 years; 6 breast, 8 colorectal cancer, and 1non^small-cell lung cancer) were entered into the study. Transient grade 1to 2 nausea and vomiting was observed following infusion of hu3S193 at the 40mg/m 2 dose level only. There was one episode of dose-limiting toxicity with self-limiting CommonToxicity Criteria grade 3 elevated alkaline phosphatase observed in one patient with extensive liver metastases. The biodistribution of 111 In-hu3S193 showed no evidence of any consistent normal tissue uptake, and 111In-hu3S193 uptake was observed in cutaneous, lymph node, and hepatic metastases. Hu3S193 displayed a long serum half-life (T 1/2 h = 189.63 F 62.17 h). Clinical responses consisted of 4 patients with stable disease and 11 patients with progressive disease, although one patient experienced a 89% decrease in a lymph node mass, and one patient experienced inflammatory symptoms in cutaneous metastases, suggestive of a biological effect of hu3S193. No immune responses (human anti-human antibody) to hu3S193 were observed. Conclusion: Hu3S193 is well tolerated and selectively targets tumors, and the long half-life and biological function in vivo of this antibody makes it an attractive potential therapy for patients with Le y -expressing cancers.

Absence of retroviral vector-mediated transformation of gene-modified T cells after long-term engraftment in mice

“…The chimeric gene was composed of extracellular singlechain anti-Le Y , [46][47][48] linked to the hinge region of CD8 followed by the transmembrane and cytoplasmic domains of CD28 and the cytoplasmic portion of CD3-z. 49 The gene was incorporated into the Moloney murine leukemia virus-based plasmid, pSAMEN.…”

Gene-modified T cells as immunotherapy for multiple myeloma and acute myeloid leukemia expressing the Lewis Y antigen

“…The safety of this approach is supported by the favorable toxicity profile of various 'naked' and conjugated anti-Le Y antibodies in early phase clinical studies, as well as the lack of transforming events in T cells retrovirally transduced to express this construct. [37][38][39][40] An alternative to the use of chimeric T cells for the treatment of Le Y expressing malignancies is the less cumbersome utilization of monoclonal antibodies. [38][39][40] However, chimeric T cells as used in this study effectively combine antigen specificity with direct activation of the most potent immune effector cells upon antigen binding.…”

“…[37][38][39][40] An alternative to the use of chimeric T cells for the treatment of Le Y expressing malignancies is the less cumbersome utilization of monoclonal antibodies. [38][39][40] However, chimeric T cells as used in this study effectively combine antigen specificity with direct activation of the most potent immune effector cells upon antigen binding. Therefore, in our opinion, chimeric T cells are more likely to mount …”

Gastric cancer stem cells: therapeutic targets

“…Conjugation of calicheamicin to hu3s193 antibody directed against Lewis y antigen (CD174), which is overexpressed on gastric carcinomas [78] as well as carcinomas of the colon, breast, lung, prostate, and ovary, demonstrated antitumor activity in vivo and caused growth arrest of xenografted gastric carcinomas for at least 100 days [79]. The first clinical trials of humanized antibody hu3s193 in patients with advanced epithelial cancer confirmed high selectivity in tumor targeting and favorable pharmacokinetics [80]. Targeting tumor cells positive for putative CSC-related markers with ADCs has the potential to eliminate CSCs as well as tumor cells without stem-like properties positive for a designated antigen.…”